4Mechanism of ActionLocal anesthetics work in general by binding to sodium channel receptors inside the cell and thereby inhibiting action potentials in a given axon. They work the best when the axon is firing.The Cell membrane consists of ion pumps, most notably the Na/K pump that create a negative 70mV resting potential by pumping 2 K+ intracellular for every 3 Na+ it pumps extracellular.
5Mechanism of Action (cont’d) If the resting potential encounters the proper chemical, mechanical or electrical stimuli to reduce the membrane potential to less than -55 mV then an action potential is produced that allows the influx of sodium ions. LA act here to block the Na influx.The influx allows the membrane potential to further increase to +35mV temporarily.Sodium and potassium channels along with the sodium/potassium pump eventually returning a given axon back to it’s resting membrane potential after an action potential.
6Mechanism of Action Benzocaine…. Does not exist in a charged form how does it work?Most likely by expanding the lipid membrane of the axon and therefore inhibiting the transport mechanisms of Na and K ions.
7General Structure A lipophilic group…usually a benzene ring A Hydrophilic group…usually a tertiary amineThese are connected by an intermediate chain that includes an ester or amide linkageLAs are weak bases
8Lipid solubility Most lipid soluble: TetracaineBupivicaineRopivacaineEtidocaineIncreased lipid solubility also equals greater potency and longer duration of action.Why?Because it has less of a chance of being cleared by blood flowDecreased lipid solubility means a faster onset of action.What else effects onset of action???
9pKaLocal anesthetics with a pKa closest to physiological pH will have a higher concentration of nonionized base that can pass through the nerve cell membrane, and generally a more rapid onset.The charged cation form more avidly binds to the Na+ channel receptors inside the cell membrane.pKa > 7.4 more cations, pKa < 7.4 more anions
10Not all Axons are equalAa- Motor with fast conduction m/s, diameter 12-20mm, myelinated and not very sensitive to local anestheticAa- Type Ia and Ib- proprioception fast conduction again m/s, same diameter as above, a little more sensitive to LA, myelinatedAb- Touch pressure and proprioception, smaller diameter 5-12mm and slower conduction 30-70m/s, myelinated and as sensitive to LA as type Ia and Ib fibers
11Not all Axons are equalAg- motor (muscle spindle) smaller diameter 3-6mm, slower conduction 15-30m/s same LA sensitivity as type Ia and Ib fibersAd- Type III fibers, pain, cold temperature and touch, smaller diameter 2-5mm, 12-30m/s, more sensitive to LA than the above fibers and myelinated.
12Not all Axons are equalB fibers- Preganglionic autonomic fibers, <3mm diameter, 3-14m/s conduction speed and very sensitive to LA. Some myelination.C fibers- Type IV fibers in the dorsal root, pain warm and cold temp. and touch, mm in diameter, slow conduction again at .5-2m/s, very sensitive to LA, not myelinated.C fibers- Postganglionic sympathetic fibers, smaller diameters at mm, slow conduction at m/s, very sensitive to LA and no myelination.In general this all means that the autonomic nerves are blocked before the sensory nerves which are blocked before the motor nerves.
13AMIDESBupivacaine, Etidocaine and Ropivacaine- very high potency and lipid solubility, very long duration and protein binding also.Lidocaine, Prilocaine and Mepivacaine- have intermediate potency and lipid solubility and intermediate duration of action and protein binding.
14ESTERSChloroprocaine and Procaine- have low potency and lipid solubility and also low duration and protein binding.Cocaine- has intermediate potency and solubility and intermediate duration and protein bindingTetracaine- has high potency and lipid solubility along with a long duration of action and high protein binding
15Plasma protein binding What protein are LAs bound???Mostly a1-acid glycoproteinTo a lesser degree albumin
16Absorption Mucous membranes easily absorb LA Skin is a different story…It requires a high water conc. for penetration and a high lipid concentration for analgesiaWhich LAs can we use for this?EMLA cream- 5% lidocaine and 5% prilocaine in an oil-water emulsionAn occlusive dressing placed for 1 hour will penetrate 3-5mm and last about 1-2 hours.Typically 1-2 grams of drug per 10cm2 of skin
17Rate of systemic absorption Intravenous > tracheal > intercostal > caudal > paracervical > epidural> brachial plexus > sciatic > subcutaneousAny vasoconstrictor present??High tissue binding also decreases the rate of absorption
18Metabolism Amides… N-dealkylation and hydroxylation P-450 enzymes, liver, slower process than esterase activityPrilocaine>lidocaine>mepivacaine>ropivacaine>bupivacainePrilocaine has a metabolite….o-toluidineThis causes methemoglobin to form (Benzocaine can also cause methemoglobin to form)Treated with methylene blue 1-2mg/kg over 5 minutesReduces methemoglobin Fe3+ to hemoglobin Fe2+
19Metabolism Esters… Procaine and benzocaine are metabolized to… PseudocholinesteraseProcaine and benzocaine are metabolized to…PABA (p-aminobenzoic acid) allergy riskTetracaine intrathecal has it’s action terminated by…No esterase activity intrathecally therefore absorption into bloodstream terminates it’s action
20Clinical UsesEstersBenzocaine- Topical, duration of 30 minutes to 1 hourChloroprocaine- Epidural, infiltration and peripheral nerve block, max dose 12mg/kg, duration 30minutes to 1 hourCocaine- Topical, 3mg/kg max., 30 minutes to one hourTetracaine- Spinal, topical, 3mg/kg max., hours duration
22Systemic ToxicityBlockage of voltaged-gated Na channel affects action potential propagation throughout the body…therefore the potential is present for systemic toxicity.Mixtures of LA have additive affectsi.e. a 50% toxic dose of lidocaine and a 50% toxic dose of bupivicaine have 100% the toxic affect of either drug
23Systemic Toxicity Neurological Symptoms include cicumoral numbness, tongue paresthesia, dizziness, tinnitus, blurred vision, restlessness, agitation, nervousness, paranoia, slurred speech, drowsiness, unconsciousness.Muscle twitching heralds the onset of tonic-clonic seizures with respiratory arrest to follow.
24Local anesthetic toxicity Seizure treatment:Thiopental 1-2mg/kg abruptly terminates seizure activityBenzos and hyperventilation…decrease CBF and therefore drug exposure. These raise the threshold of local anesthetic-induced seizuresChloroprocaine injected intrathecally can cause prolonged neurotoxicity. This is likely due to a preservative no longer used with this agent. (Sodium bisulfate)
25Local anesthetic toxicity Repeated doses of 5% lidocaine and .5% tetracaine may be responsible for cauda equina syndrome following infusion through small bore catheters in spinal anesthetics.Pooling of drug around the cauda equina resulted in permanent neurological damageAnimal studies suggest that neuro damage is: Lido=tetracaine>bupivacaine>ropivacaine. Also perservative free chloroprocaine may be neurotoxic
26Local anesthetic toxicity Transient Neurological SymptomsThis is associated with dysethesia, burning pain and aching in lower ext, buttocks.Follows spinal anesthesia with variety of agents (lido), attributed to radicular irritation and resolves in 1 week usuallyRisk factors includeLidocaine intrathecallyLithotomy positionObesityOutpatient statusUnpleasant abnormal sensation
27Local anesthestic toxicity Respiratory center may be depressed (medullary)…postretrobulbar apnea syndromeLidocaine depresses hypoxic respiratory drive (PaO2)Direct paralysis of phrenic or intercostal nerves
28LA cardio toxicityAll LA’s depress spontaneous Phase IV depolarization and reduce the duration of the refractory periodMyocardial contractility and conduction velocity are depressed at higher concentrationsAll LA’s except cocaine cause smooth muscle relaxation and therefore vasodilation (art) whick can lead to brady, heart block and hypotension…cardiac arrest.
29LA cardio toxicityMajor cardiovascular toxicity usually results from 3 times the blood concentration of LA that causes seizures.Therefore cardiac collapse is usually the presenting sign under GA.R isomer of bupivacaine avidly blocks cardiac sodium channels and dissociates very slowly. Making resuscitation prolonged and difficult.
30LA cardio toxicityLevo-bupivacaine (S isomer) is no longer avaliable in the US but had a cardiovascular profile similar to ropivacaine.Ropivacaine has a larger therapeutic index and it is 70% less likely to cause severe cardiac dsyrhythmias than bupivacaineAlso ropviacaine has greater CNS toleranceThe improved safety profile is due to a lower lipid solubility
31LA toxicity treatmentSupportive care: intubation, vasopressors, appropriate defibrillation, fluids, stop injection of LA, anything else….Intralipid…Bolus 1cc/kg of 20% intralipid, 0.25cc/kg/min of 20% intralipid for 10 minutesBolus can be repeated every 5 minutes up to a maximum of 8cc/kg of 20% intralipidCardiac support should be continued as ACLS dictatesEpi and vasopresin should likely both be used in the resusitation efforts (animal model data from A & A)
32Lipid, Not Propofol, Treats Bupivacaine Overdose Guy Weinberg, MD, Paul Hertz, MD, and Janet Newman, MD Department of Anesthesiology, University of Illinois, Chicago, IL,To the Editor:Mayr et al. (1) recently reported the comparative efficacies of epinephrine, vasopressin, and a combination of the two drugs in a porcine model of bupivacaine overdose. They used a single 5 mg/kg IV bolus of bupivacaine, applied advanced cardiac life support 1 min after asystole, and administered drugs 2 min later and at 5-min intervals thereafter. Monophasic countershocks were applied as dictated by rhythm disturbance. Rates of survival were 5/7 for vasopressin, 4/7 for epinephrine, 7/7 in the combined treatment group, and 0/7 in controls.By comparison, we reported that injecting a 20% lipid emulsion in combination with cardiac massage leads to successful return of normal hemodynamics in 9/9 dogs after a bolus injection of 10 mg/kg bupivacaine (2). Lipid infusion in 6 of these dogs was delayed for 10 min to approximate a clinical scenario. A normal rhythm was established in all 9 dogs within 5 min; no electrical counter shock was required. No control animal demonstrated return of BP or HR.Dogs and pigs may differ in terms of susceptibility to bupivacaine cardiac toxicity; the porcine and canine models may not be completely comparable for this and other reasons. However, we and others (3) believe the rapid return of normal rhythm and hemodynamics in both dogs and rats following massive bupivacaine overdose (twice the dose used in Mayr’s study), indicates superior efficacy of lipid rescue for bupivacaine toxicity to drugs, such as epinephrine and vasopressin that are components of the generic ACLS protocol for cardiopulmonary arrest (4). Perhaps Dr. Mayr will consider comparing combined epinephrine/vasopressin with lipid rescue in the porcine model of bupivacaine cardiac toxicity.Mayr et al. (1) also incorrectly cite us as indicating that "....a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and, therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity." We have never recommended use of propofol for treating bupivacaine overdose, and strongly suspect that its use in cardiac arrest will impede resuscitation.We have recommended treating bupivacaine-associated cardiac arrest by injecting a 1 mL/kg bolus of 20% lipid emulsion (such as Intralipid) and starting an infusion of 0.25 mL/kg/min for 10 min, while continuing basic life support (5). The bolus could be repeated every 5 min, two or three times if needed. The upper dose limit of 20% lipid emulsion is not known, but a total of more than 8 mL/kg is not likely to be needed, nor successful if lower doses are not. Note that this protocol will deliver a significant volume load (several hundred mL in an adult). The standard formulation of propofol is 10% lipid and 1% propofol. Therefore, gram quantities of propofol would accompany our recommended regimen and only half the dose of lipid, the necessary ingredient, would be delivered.Propofol is not an acceptable treatment for bupivacaine overdose.ReferencesMayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid intravenous injection of bupivacaine. Anesth Analg 2004; 98: 1426–31.[Abstract/Free Full Text]Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198–202.[ISI][Medline]Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2003; 28: 167–9.[ISI][Medline]Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 2: toxicology in ECC. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000; 102 (suppl 8): I223–8.[Medline]Weinberg G. Lipid rescue: caveats and recommendations for the "Silver Bullet" [letter]. Reg Anesth Pain Med 2004; 29: 74–5. ResponseViktoria D. Mayr, MD, Claus Raedler, MD, Volker Wenzel, MD, Karl H. Lindner, MD, and Hans-Ulrich Strohmenger, MD Univ. Klinik f. Anaesthesie u. Allg. Intensivmedezin, Innsbruck, Austria,In Response:We would like to thank Weinberg et al. for their interest in our work, as well as for their constructive comments. First, we sincerely apologize for having incorrectly cited Weinberg et al. by confounding propofol and intralipid; we completely agree with their statement that propofol administration cannot be recommended for managing a bupivacaine overdose. When indicating in the Discussion section that "... a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity," we did not suggest to use propofol for treating bupivacaine toxicity, nor that Dr. Weinberg et al. used propofol for treating bupivacaine toxicity. We share the same opinion that usage of propofol in cardiac arrest may impede resuscitation. With our statement about a "lipid infusion such as propofol...", we only wanted to state the reason why we did not use propofol but isoflurane and nitrous oxide to maintain anesthesia in our experiment. Instead of saying "... a lipid infusion such as propofol...", it would have been better to state "... as propofol is a lipid infusion which may increase the dose of bupivacaine required to induce cardiac arrest..." Second, beneficial lipid effects during massive bupivacaine overdose as described by Weinberg et al. resulted in impressive outcome data. However, their conclusion drawn in the letter that these results indicate the superiority of this treatment regime in comparison to advanced cardiac life support including epinephrine and vasopressin has not been proven. The comparative investigation of the epinephrine/vasopressin combination and the lipid rescue protocol in the same animal model of bupivacaine cardiac toxicity can only provide reliable information in this respect.
33True Allergic Reactions to LA’s Very uncommonEsters more likely because of p-aminobenzoic acid (allergen)Methylparaben preservative present in amides is also a known allergen
34Local Anesthetic Musculoskeletal Cause myonecrosis when injected directly into the muscleWhen steroid or epi added the myonecrosis is worsenedRegeneration usually takes 3-4 weeksRopivacaine produces less sereve muscle injury than bupivacaine
35Drug InteractionsChloroprocaine epidurally may interfere with the analgesic effects of intrathecal morphineOpioids and a2 agonists potentiate LA’sPropranolol and cimetidine decrease hepatic blood flow and decrease lidocaine clearancePseudocholinesterase inhibitors decrease Ester LA metabolismDibucaine (amide LA) inhibits pseudocholinesterase used to detect abn enzymeSux and ester LA need pseudochol. for metabolism therefore adminstering both may potentiate their activityLA potentiate nondepolarizing muscle relaxant blockade
36Other agents with LA properties MeperidineTCAs (amitriptyline)Volatile anestheticsKetamineTetrodotoxin (blocks Na channels from the outside of the cell membrane) Animal studies suggest that when used in low doses with vasoconstrictors it will significantly prolong duration of action of LA.
37BibliographyClinical Anesthesiology, Morgan and Mikhail